JP4190288B2 - （１ｒｓ，２ｒｓ）−２−［（ジメチルアミノ）メチル］−１−（３−メトキシフェニル）シクロヘキサノールを単離および精製する方法 - Google Patents
（１ｒｓ，２ｒｓ）−２−［（ジメチルアミノ）メチル］−１−（３−メトキシフェニル）シクロヘキサノールを単離および精製する方法 Download PDFInfo
- Publication number
- JP4190288B2 JP4190288B2 JP2002565932A JP2002565932A JP4190288B2 JP 4190288 B2 JP4190288 B2 JP 4190288B2 JP 2002565932 A JP2002565932 A JP 2002565932A JP 2002565932 A JP2002565932 A JP 2002565932A JP 4190288 B2 JP4190288 B2 JP 4190288B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- cyclohexanol
- dimethylamino
- methoxyphenyl
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 57
- TVYLLZQTGLZFBW-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol Chemical compound COC1=CC=CC(C2(O)C(CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 43
- CVHZOJJKTDOEJC-UHFFFAOYSA-M 1,1-dioxo-1,2-benzothiazol-3-olate Chemical compound C1=CC=C2C([O-])=NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-M 0.000 claims abstract description 14
- 239000002244 precipitate Substances 0.000 claims description 29
- 239000012429 reaction media Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims description 16
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 15
- 229940081974 saccharin Drugs 0.000 claims description 15
- 235000019204 saccharin Nutrition 0.000 claims description 15
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000003747 Grignard reaction Methods 0.000 claims description 14
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 14
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 12
- TVYLLZQTGLZFBW-GOEBONIOSA-N (S,S)-tramadol Chemical compound COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000012452 mother liquor Substances 0.000 claims description 10
- -1 aliphatic ester Chemical class 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 150000002894 organic compounds Chemical class 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- TVYLLZQTGLZFBW-GDBMZVCRSA-N (1s,2r)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol Chemical compound COC1=CC=CC([C@@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GDBMZVCRSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 229920005862 polyol Polymers 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000006227 byproduct Substances 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 150000003077 polyols Chemical class 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 238000010908 decantation Methods 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000011877 solvent mixture Substances 0.000 claims 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 1
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 claims 1
- QDHLEFBSGUGHCL-UHFFFAOYSA-N 2-[(dimethylamino)methyl]cyclohexan-1-one Chemical compound CN(C)CC1CCCCC1=O QDHLEFBSGUGHCL-UHFFFAOYSA-N 0.000 claims 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims 1
- HBGGXOJOCNVPFY-UHFFFAOYSA-N diisononyl phthalate Chemical compound CC(C)CCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCC(C)C HBGGXOJOCNVPFY-UHFFFAOYSA-N 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 238000007670 refining Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 9
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UUKWKUSGGZNXGA-UHFFFAOYSA-N 3,5-dinitrobenzamide Chemical compound NC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 UUKWKUSGGZNXGA-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000003839 salts Chemical group 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10108308A DE10108308A1 (de) | 2001-02-21 | 2001-02-21 | Verfahren zur Isolierung und Reinigung von (1RS,2RS)-2[(Dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol |
| PCT/EP2002/001764 WO2002066414A1 (de) | 2001-02-21 | 2002-02-20 | Verfahren zur isolierung und reinigung von (1rs,2rs)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2004524306A JP2004524306A (ja) | 2004-08-12 |
| JP4190288B2 true JP4190288B2 (ja) | 2008-12-03 |
Family
ID=7674966
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002565932A Expired - Fee Related JP4190288B2 (ja) | 2001-02-21 | 2002-02-20 | （１ｒｓ，２ｒｓ）−２−［（ジメチルアミノ）メチル］−１−（３−メトキシフェニル）シクロヘキサノールを単離および精製する方法 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US6909017B2 (hu) |
| EP (1) | EP1363872B1 (hu) |
| JP (1) | JP4190288B2 (hu) |
| AT (1) | ATE405541T1 (hu) |
| AU (1) | AU2002253040B2 (hu) |
| CA (1) | CA2437117C (hu) |
| DE (2) | DE10108308A1 (hu) |
| ES (1) | ES2312562T3 (hu) |
| HU (1) | HUP0303302A3 (hu) |
| MX (1) | MXPA03007478A (hu) |
| NZ (1) | NZ528135A (hu) |
| PL (1) | PL207042B1 (hu) |
| WO (1) | WO2002066414A1 (hu) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102005033732B4 (de) * | 2005-05-27 | 2014-02-13 | Grünenthal GmbH | Trennung stereoisomerer N,N-Dialkylamino-2-alkyl-3-hydroxy-3-phenyl-alkane |
| EP1785412A1 (en) | 2005-11-14 | 2007-05-16 | IPCA Laboratories Limited | Tramadol recovery process |
| CN105884630B (zh) * | 2016-04-18 | 2018-06-01 | 镇江高海生物药业有限公司 | 一种盐酸文拉法辛的有关物质及其分析检测方法 |
| FR3074497B1 (fr) | 2017-12-06 | 2020-09-11 | Total Marketing Services | Composition d’additifs pour carburant |
| KR20230081285A (ko) * | 2021-11-30 | 2023-06-07 | 주식회사 브이에스팜텍 | 고순도의 1-(1-(2-벤질페녹시)프로판-2-일)-2-메틸피페리딘 단일 이성질체의 제조방법 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3652589A (en) | 1967-07-27 | 1972-03-28 | Gruenenthal Chemie | 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols |
| IL116281A (en) * | 1995-12-07 | 1999-06-20 | Chemagis Ltd | Process for the purification of (rr,ss)-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol and its salts |
| US5877351A (en) * | 1997-12-24 | 1999-03-02 | Wyckoff Chemical Company, Inc. | Preparation and purification process for 2- (dimethylamino) methyl!-1-(3-methoxphenyl)-cyclohexanol and its salts |
| WO1999061405A1 (en) | 1998-05-22 | 1999-12-02 | Mallinckrodt Inc. | An improved synthesis and purification of (r*,r*)-2-[ (dimethylamino) methyl]-1-( 3-methoxyphenyl) cyclohexanol hydrochloride |
| JP2003502400A (ja) * | 1999-06-22 | 2003-01-21 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | ２−［（ジメチルアミノ）メチル］−１−（３−メトキシフェニル）−シクロヘキサノールのジアステレオマー塩基の分割方法 |
| DE19940740A1 (de) * | 1999-08-31 | 2001-03-01 | Gruenenthal Gmbh | Pharmazeutische Salze |
-
2001
- 2001-02-21 DE DE10108308A patent/DE10108308A1/de not_active Ceased
-
2002
- 2002-02-20 EP EP02722103A patent/EP1363872B1/de not_active Expired - Lifetime
- 2002-02-20 NZ NZ528135A patent/NZ528135A/en not_active IP Right Cessation
- 2002-02-20 HU HU0303302A patent/HUP0303302A3/hu unknown
- 2002-02-20 JP JP2002565932A patent/JP4190288B2/ja not_active Expired - Fee Related
- 2002-02-20 AT AT02722103T patent/ATE405541T1/de active
- 2002-02-20 AU AU2002253040A patent/AU2002253040B2/en not_active Ceased
- 2002-02-20 CA CA2437117A patent/CA2437117C/en not_active Expired - Fee Related
- 2002-02-20 DE DE50212672T patent/DE50212672D1/de not_active Expired - Lifetime
- 2002-02-20 ES ES02722103T patent/ES2312562T3/es not_active Expired - Lifetime
- 2002-02-20 WO PCT/EP2002/001764 patent/WO2002066414A1/de active IP Right Grant
- 2002-02-20 MX MXPA03007478A patent/MXPA03007478A/es active IP Right Grant
- 2002-02-20 PL PL362289A patent/PL207042B1/pl not_active IP Right Cessation
-
2003
- 2003-08-11 US US10/638,703 patent/US6909017B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1363872A1 (de) | 2003-11-26 |
| MXPA03007478A (es) | 2003-12-04 |
| PL362289A1 (en) | 2004-10-18 |
| JP2004524306A (ja) | 2004-08-12 |
| HUP0303302A3 (en) | 2007-03-28 |
| HUP0303302A2 (hu) | 2004-01-28 |
| EP1363872B1 (de) | 2008-08-20 |
| US6909017B2 (en) | 2005-06-21 |
| AU2002253040B2 (en) | 2006-09-28 |
| DE50212672D1 (de) | 2008-10-02 |
| PL207042B1 (pl) | 2010-10-29 |
| NZ528135A (en) | 2005-03-24 |
| WO2002066414A1 (de) | 2002-08-29 |
| ES2312562T3 (es) | 2009-03-01 |
| ATE405541T1 (de) | 2008-09-15 |
| US20040225154A1 (en) | 2004-11-11 |
| CA2437117A1 (en) | 2002-08-29 |
| DE10108308A1 (de) | 2002-08-29 |
| CA2437117C (en) | 2010-11-30 |
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